First application of an efficient and versatile ligand for copper-catalyzed cross-coupling reactions of vinyl halides with N-heterocycles and phenols

Article abstract of DOI:10.1021/ol9026446

[Chemical equaction presented] 2-Pyridin-2-yl-1H-benzoimidazole L3 is presented as a new, efficient, and versatile bidentate N-donor ligand suitable for the copper-catalyzed formation of vinyl C N and C O bonds. This inexpensive and easily prepared ligand facilitates copper-catalyzed cross-coupling reactions of alkenyl bromides and Iodldes with N-heterocycles and phenols to afford the desired cross-coupled products In good to excellent yields with full retention of stereochemistry. This method is particularly noteworthy given Its efficiency, that is, mild reaction conditions, low catalyst loading, simplicity, versatility, and exceptional level of functional group tolerance.

Full text of DOI:10.1021/ol9026446

ORGANIC
LETTERS
2010
Vol. 12, No. 3
464-467
First Application of an Efficient and
Versatile Ligand for Copper-Catalyzed
Cross-Coupling Reactions of Vinyl
Halides with N-Heterocycles and
Phenols
M. Shahjahan Kabir, Michael Lorenz, Ojas A. Namjoshi, and James M. Cook*
Department of Chemistry and Biochemistry, UniVersity of Wisconsin-Milwaukee,
Milwaukee, Wisconsin 53201
capncook@uwm.edu
Received November 16, 2009
ABSTRACT
2-Pyridin-2-yl-1H-benzoimidazole L3 is presented as a new, efficient, and versatile bidentate N-donor ligand suitable for the copper-catalyzed
formation of vinyl C-N and C-O bonds. This inexpensive and easily prepared ligand facilitates copper-catalyzed cross-coupling reactions of
alkenyl bromides and iodides with N-heterocycles and phenols to afford the desired cross-coupled products in good to excellent yields with
full retention of stereochemistry. This method is particularly noteworthy given its efficiency, that is, mild reaction conditions, low catalyst
loading, simplicity, versatility, and exceptional level of functional group tolerance.
In the past few years, significant progress has been made on
the development of copper-catalyzed Ullmann-type coupling
reactions for the synthesis of aryl amines, aryl ethers, aryl
thioethers, and vinyl amides.1 In contrast, only a few methods
have appeared for the copper-catalyzed synthesis of vinyl
amines and vinyl ethers of synthetic, polymeric, and biologi-
cal importance.2
esting biological activity contain the N-vinyl heterocycle and
aryl vinyl ether moieties.2
Recent studies in our laboratory indicated that ligands such
as N-vinyl heterocycles, aryl vinyl ethers, and aryl vinyl
thioethers are active against drug resistant strains of tuber-
culosis, anthrax, and many other strains of drug-resistant
Gram-positive bacteria.3 Many of these active compounds
require electron donating groups (EDG) in both halves of
the molecule.3d One portion of these ligands must contain
the structural framework A illustrated in Scheme 1. This
substitution pattern was required for potent activity of this
new class of antibacterials.3c Due to the importance of these
N-vinyl heterocycles and vinyl ether moieties, there have
been a number of methods reported regarding their synthe-
ses.4 More often than not, all of these methods require harsh
reaction conditions and are complicated by substrate limita-
The vinyl group itself is of fundamental importance in
organic chemistry. N-Vinyl amines are widely used in the
preparation of polymeric dyes, catalysis, and ion-exchange
resins; while aryl vinyl ethers are useful intermediates in a wide
variety of reactions (e.g., cycloaddition, cyclopropanation, and
metathesis processes),2 as well as in the synthesis of polymers.2
In addition, the vinyl group can act as an efficient
protecting group of N-heterocycles and phenol derivatives.2
Many natural products and compounds which exhibit inter-
10.1021/ol9026446  2010 American Chemical Society
Published on Web 12/29/2009

vinylations require moderate reaction conditions (60-110
°C),2a,b one of their major drawbacks is longer reaction times
(24-36 h) and poor applicability for triazole and tetrazole
nucleophiles. For example, this longer reaction time, in many
cases, is a major problem with highly electron rich substrates,
such as those of interest in the structural framework A
illustrated in Scheme 1. Earlier attempts to synthesize these
electron rich substrates using moderate reaction conditions2a,b
and longer reaction times routinely gave a considerable
amount of aryl acetylene byproducts (35-65%) and conse-
quently, low yields of the desired product. During the
execution of these studies a relatively shorter process (4-10
h) and a more moderate temperature [(82 °C) Cu-catalyzed
vinylation] has appeared in the literature.2d In our studies,
we recently reported a Cu(I) catalytic system in combination
with the ligand cis-1,2-hexanediol which employed moderate
reaction conditions and shorter reaction times for the
vinylation of thiols.3a Unfortunately, this system proved
ineffective for N- and O- vinylations.
Scheme 1
.
Generalized Cu-Catalyzed Coupling Reaction with
Electron Rich Systems
tions.4 Furthermore, the practical application of these meth-
ods often leads to a mixture of Z and E isomers.4
The most efficient methods currently for the synthesis of
N-vinyl heterocycles and aryl vinyl ethers are based upon
transition-metal-mediated coupling reactions of N-heterocy-
cles and phenols with different vinyl sources. Z and E Hg5
and Pd-mediated6 preparations of vinyl azoles and vinyl
ethers are notable in this case. The toxicity of mercury and
the high cost of Pd, as well as the latter’s air sensitivity,
potentially limit their use for many industrial applications.
A few reports on the Cu-catalyzed vinylation of N-
heterocyclces, phenols, and thiols have appeared in the past
few years. Some of these vinylations require either a
stoichiometric Cu-source7a-c or high catalyst loading, as well
as harsh reaction conditions.7d-g Although a few of these
A potential solution was envisioned by use of an alterna-
tive Cu(I) catalytic system which would work for substrates
related to that of A in Scheme 1 under mild conditions.
Herein, we report the development of a new Cu(I) catalytic
system and its application as a versatile, rapid, efficient, and
stereospecific method for the synthesis of N-vinyl hetero-
cycles and aryl vinyl ethers.
(1) (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
6954(Minireview) and references cited therein. (b) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400(Review) and references cited
therein. (c) Ley, S. V.; Thomas, A. W. Angew. Chem. 2003, 115, 5558. (d)
Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (e) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (f) Fraln, R.; Kikeji,
D. Synthesis 2006, 2271. (g) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006,
106, 2651. (h) Kienle, M.; Dubakka, S. R.; Brade, K.; Knochel, P. Eur. J.
Org. Chem. 2007, 4166. (i) Carril, M.; SanMartin, R.; Dominguez, E. Chem.
Soc. ReV. 2008, 37, 639. (j) Shafir, A.; Lichtor, P. A.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 3490. (k) Altman, R. A.; Buchwald, S. L.
Org. Lett. 2007, 9, 643. (l) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2003, 5, 3667. (m) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315. (n) Harada, H.; Thalji, R. K.;
Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772. (o) Nordmann,
G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978. For intamolecular
Ullmann Coupling, please see also: (p) Chemler, S. R.; Fuller, P. H. Chem
Soc. ReV. 2007, 36, 1153. (q) Evano, G.; Blanchard, N.; Toumi, M. Chem.
ReV 2008, 108, 3054. For a highlight on recent major developments in C-C,
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Chem., Int. Ed. 2008, 47, 3096, and references cited therein. (s) Chen, Y.-
G.; Chen, H.-H. Org. Lett. 2006, 8, 5609. For vinylation of amide,s please
see these leading references: (t) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004,
6, 1809. (u) Smith, A. B., III; Duffey, M. O.; Basu, K.; Walsh, S. P.;
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C. T.; Bowman, E. J.; Bowman, B. J.; Proco, J. A., Jr. J. Am. Chem. Soc.
2003, 125, 7889. (y) Huang, X.; Shao, N.; Huryk, R.; Palani, A.; Aslanian,
R.; Seidel-Dugan, C. Org. Lett. 2009, 11, 867. (z) Cesati, R. R., III; Dwyer,
G.; Jones, R. C.; Hayes, M. P.; Yalamanchili, P.; Casebier, D. S. Org. Lett.
2007, 9, 5617. Other contributors were cited in the aforementioned
referenced reviews and minireviews.
The initial ligand screening and optimization studies for
the O-vinylation of phenols were conducted on a simpler
substrate, a phenyl vinyl iodide, because it was devoid of
any electron withdrawing group (EWG) or EDG (see
Supporting Information) groups. The 2-isopropylphenol was
used as the prototypical nucleophilic substrate for these
optimization experiments.8 Ultimately, a new ligand, 2-py-
ridin-2-yl-1H-benzoimidazole (L3) gave superior results
when used in an equimolar concentration with 5 mol % Cu(I),
and 2.0 equivalents of Cs2CO3 in reagent grade DMF
(without drying or degassing). Moreover, in contrast to DMF
the solvents DME, iPrOH and 1,4-dioxane proved to be
ineffective. Interestingly, the normally unstable aryl vinyl
halides which contain EDG in framework A (Scheme 1) were
found to be stable to some extent in DMF. Thus, the above-
mentioned reaction conditions with CuI and L3 proved to
be the best for the vinylation of phenols to furnish the desired
aryl vinyl ethers with little or no formation of the aryl
acetylene byproduct.
The exceptional activity of CuI with L3 is, presumably,
due to the required electron density on Cu provided by ligand
L3 for the vinylation of phenols. In addition, the resulting
Cu-L3 complex may be conformationally less rigid than
(2) (a) Taillefer, M.; Ouali, A.; Renard, B.; Spindler, J.-F. Chem.sEur.
J. 2006, 12, 5301. (b) Bao, W.; Xin Lv, Y. L. Synthesis 2008, 12, 1911. (c)
Ouali, A.; Laurent, R.; Caminade, A.-M.; Majoral, J.-P.; Taillefer, M. J. Am.
Chem. Soc. 2006, 128, 15990. (d) Kaddouri, H.; Vicente, V.; Ouali, A.;
Ouazzani, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 333.
(3) (a) Kabir, M. S.; Van Linn, M. L.; Monte, A.; Cook, J. M. Org.
Lett. 2008, 10, 3363. (b) Kabir, M. S.; Monte, A.; Cook, J. M. Tetrahedron
Lett. 2007, 48, 7269. (c) Kabir, M. S.; Kathleen, E.; Rebecca, P.; Krueger,
S. M.; Ignasiak, R.; Rott, M.; Schwan, W. R.; Stemper, M. E.; Reed, K. D.;
Sherman, D.; Cook, J. M.; Monte, A. Bioorg. Med. Chem. Lett. 2008, 18,
5745. (d) Monte, A.; Kabir, M. S.; Cook, J. M.; Rott, M.; Schwan, W. R.;
Defoe, L. U.S. Pat. Appl. Publ. 2007, 37.
(4) (a) Reference 2a and references cited therein. (b) Okimoto, Y.;
Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2002, 124, 1590. (c) Crivello,
J. V.; Kong, S. J. Org. Chem. 1998, 63, 6745. (d) Suprenant, S.; Chan,
W. Y.; Berthelette, C. Org. Lett. 2003, 5, 4851.
(5) (a) Kizhnyae, V. N.; Pokatilov, F. A.; Tsypina, N. A.; Ratovskii,
G. V.; Vereshchagin, L. I.; Smirnov, A. I. Russ. J. Org. Chem. 2002, 38,
1056. (b) Chen, Y. L.; Hedberg, K. G.; Guarino, K. J. Tetrahedron Lett.
1989, 30, 1067.
(6) (a) Lebedev, A. Y.; Izmer, V. V.; Kazyul’kin, D. N.; Beletskaya,
I. P.; Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623–626. (b) Willis, M. C.;
Taylor, D.; Gillmore, A. T. Chem. Commun. 2003, 2222.
Org. Lett., Vol. 12, No. 3, 2010
465

the other ligands screened to date (see Supporting Informa-
tion) and provided, presumably, a more planar coordination
of the Cu(I) cation.9
Encouraged by these early results, these reaction conditions
were employed for the coupling of various aryl vinyl halides
with N-heterocycles including indole, pyrazole, imidazole,
indazole, benzotriazole, and tetrazoles (Tables 1 and 2).
Table 2. Stereospecific Cu-Catalyzed Cross-Coupling of
(Z)-Ethyl 3-Iodo-acrylate with Various N-Heterocycles
Table 1. Cu-Catalyzed Cross-Coupling of Various (E)-Aryl
Alkenyl Iodides with N-Heterocycles
a Isolated yields, the average of at least two runs. b The reaction was
carried out at 60 °C and was stirred for 6 h.
although reactions with aryl vinyl bromides required a little
longer reaction time for complete consumption of starting
material (Table 1, entries 1-3).
To demonstrate the effectiveness of the new ligand catalyst
system, highly electron rich aryl vinyl iodides which
contained a silyl-protected hydroxy group at the 3-position
and a methoxy substituent at the 5-position (Table 1, entries
4-8) gave coupling products in excellent yield without the
formation of any aryl acetylene byproducts (cf. Scheme 1).
This is in contrast to cases which employed the other nitrogen
based ligands and catalysts (see Supporting Information) and
gave considerable amounts of aryl acetylene byproduct and/
or loss of the silyl protecting group before the completion
of the coupling due to higher reaction temperatures.
This premature loss of the silyl group caused by the harsh
reaction conditions noted previously4 made the isolation of
coupled products from deprotected aryl vinyl iodide and its
eliminated byproduct very difficult. The presence of the
deprotected phenolic vinyl iodide gave more of the acetylene
byproduct that was difficult to separate. In contrast, when
ligand L3 and the new conditions were employed, which
a Isolated yields, the average of at least two runs. b The starting aryl
vinyl halides contained ∼3-9% Z-isomer; this resulted in ∼3-9% of the
cis-isomer, reflected in the overall yield. c The reaction was carried out at
80 °C and was stirred for 10 h. d Treatment with TBAF·THF provided the
desired N-vinyl heterocycles.
(7) (a) Lam, P.Y. S.; Vincent, G.; Bonne, D.; Clark, C. G.; Deudon, S.
Tetrahedron Lett. 2003, 44, 4927. (b) Lam, P.Y. S.; Vincent, G.; Clark,
C. G.; Deudon, S.; Lam, P. Y. S.; Vincent, G.; Jadhav, P. K. Tetrahedron
Lett. 2001, 42, 3415. (c) Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66,
9043. (d) Wan, Z.; Jones, C. D.; Koenig, T. M.; Pu, Y. J.; Mitchell, D.
Tetrahedron Lett. 2003, 44, 8257. (e) Ma, D.; Cai, Q.; Xie, X. Synlett 2005,
11, 1767. (f) Shen, G.; Lv, X.; Qian, W.; Bao, W. Tetrahedron Lett. 2008,
49, 4556. (g) Wang, Z.; Bao, W.; Jiang, Y. Chem. Commun. 2005, 2849.
(h) Mao, J.; Hua, Q.; Guo, J.; Shi, D.; Ji, S. Synlett 2008, 13, 2011.
(8) Optimization studies of the reaction conditions were accomplished with
nitrogen and oxygen nucleophiles in parallel experiments which led to the same
results in terms of yields. For reasons of chemical economy, more conditions
were screened in the cases of oxygen nucleophiles (see Suppoting Information)
and the best results extended to the nitrogen nucleophiles.
Interestingly, (Z)-ethyl-3-iodo-acrylate (Table 2) gave the
desired N-vinylations at relatively lower temperatures (40 °C)
and shorter reaction times (3-4 h) as compared to the (E)-
vinyl halides (Table 1). This may be due to electronic or steric
effects which are under study at present. All reactions shown
in Tables 1 and 2 proceeded in good to excellent yields with
full retention of stereochemistry. The reaction of aryl vinyl
bromides also gave full conversions similar to aryl vinyl iodides,
(9) Zeng, M.-H.; Shen, X.-C.; Ng, S. W. Acta Crystallogr. 2006, E62,
2194.
466
Org. Lett., Vol. 12, No. 3, 2010

were much milder, the silyl function remained intact to
provide the coupled products in high yield. Deprotection was
then carried out in the same reaction vessel using TBAF·THF
again in high yield, as expected (entries 4-8, Table 1). The
scope of this process was extended by using trifluoromethyl-
substituted (EWG) aryl vinyl iodides for the N-vinylations
and found again to provide excellent yields (entries 9-12,
Table 1) of the N-vinyl heterocycles.
The ability to couple E-aryl vinyl halides with phenols
was also investigated and CuI/L3/Cs2CO3/DMF proved to
be an excellent catalytic system for the vinylation of phenols
as well (Table 3), albeit this required somewhat higher
The stereochemistry in all ethers was retained regardless
of the (E)- or (Z)-configuration. To ensure the coupling
reaction proceeded in a stereospecific fashion, the process
was investigated using the (Z)-vinyl iodide, ethyl cis-3-iodo-
acrylate, in the presence of various phenols. Interestingly,
examination of the results indicated that the reaction of (Z)-
vinyl iodides proceeded more rapidly and under milder
conditions (i.e., rt in 2-6 h or 40 °C in 30 min) than the
corresponding (E)-isomers. This functionalized (Z)-vinyl
iodide gave excellent yields with complete retention of
stereochemistry regardless of whether electron rich or electron
poor aryl- and heterocyclic phenols were used (Table 4).
Table 3. Cu-Catalyzed Cross-Coupling of Various (E)-Aryl
Alkenyl Halides with Phenols
Table 4. Stereospecific Cu-Catalyzed Cross-Coupling of
(Z)-Ethyl 3-Iodo-acrylate with Various Phenols
a Isolated yields, the average of at least two runs.
In summary, an efficient, stereospecific Cu-mediated catalytic
system (CuI/L3) has been developed for the synthesis of N-vinyl
heterocycles and aryl vinyl ethers. Ligand L3 was shown to be
very effective in these processes. This method is useful because
of the mild reaction conditions, broad functional group tolerance,
stereospecificity, low catalyst loading, simplicity, and efficiency.
Further investigation of the utility of this Cu(I) catalytic system
as well as the importance of L3 is currently in progress.
Acknowledgment. We thank Dr. Steven. H. Bertz Com-
plexity Study Center, Mendham, New Jersey for helpful
discussions, Dr. M. E. Dudley, Marquette University, for
technical advice and the NIH as well as The Research
Growth Initiative of the University of Wisconsin-Milwaukee
for financial support.
a Isolated yields, the average of at least two runs. b The starting aryl
vinyl halides contained ∼ 3-9% Z-isomer, this led to ∼3-9% of the cis-
isomer, reflected in the overall yield. c The reaction was carried out at 80
°C and was stirred for 10 h. d Treatment with TBAF·THF provided the
desired aryl vinyl ether.
Supporting Information Available: Detailed experimental
procedure, ligand preparation, screening, and optimization and
characterization data of each compound. This material is
available free of charge via the Internet at http://pubs.acs.org.
temperatures (70-80 °C) and slightly longer reaction times
(7-10 h). Vinyl bromides (Table 3, entries 1-3) were found
to require longer reaction times (10 h) in comparison to the
corresponding vinyl iodides (7 h), as expected.
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